Obesity is now understood to be a systemic inflammatory disease that correlates with cellular immune dysregulation. Recent evidence suggests bariatric surgery, including laparoscopic sleeve gastrectomy (LSG), produces not just weight loss but also beneficial effects on immunometabolism.
Eric G. Sheu, MD, PhD, a surgeon in the Laboratory for Surgical and Metabolic Research at Brigham and Women’s Hospital, Tammy Lo, MBBS, a fellow in the laboratory, Damien C. Croteau-Chonka, PhD, an associate epidemiologist in the Channing Division of Network Medicine, and colleagues explored how LSG improves the systemic inflammatory profile.
In The Journal of Clinical Endocrinology & Metabolism, they describe pronounced improvement in immune cell composition, function and metabolism, as measured by both biomarkers and gene expression, as soon as three months after the procedure.
Methods
The prospective study involved 23 patients who underwent LSG at the Brigham between January 2017 and July 2019. The average age was 44, and 78% of patients were female. None of the patients had a preexisting autoimmune disease or were using immunomodulatory treatment.
Patients provided whole blood samples at five evenly spaced intervals: at baseline and three, six, nine, and 12 months postoperatively.
Leukocyte Profiles and Markers of Inflammation
The researchers observed recovery of the immune system from a chronic inflammatory state. Most improvements in plasma markers were already significant at the three-month postoperative visit (T3) and persisted throughout the follow-up period:
- White blood cells—9.4 K/microliter at baseline, 6.7 K/microliter at T3 (P<0.001), and 5.9 K/microliter (P<0.05) at T12
- Neutrophils—6.7 K/microliter at baseline, and 3.8 K/microliter (P<0.05) at T3
- C-reactive protein—7.0 mg/L at baseline, 4.7 mg/L (P≥0.05) at T3, and 2.4 mg/L (P<0.05) at T12
- Interleukin-6—5.4 pg/mL at baseline, and 4.3 pg/mL (P≥0.05) at T3
The early decrease in neutrophils was paired with a steady level of lymphocytes. Thus, the neutrophil–lymphocyte ratio (NLR) decreased, indicating a more lymphocyte-mediated adaptive immunity.
Hormonal Biomarkers of Metabolism
Concentrations of gut hormones were also reduced:
- Leptin—70.3 ng/mL at baseline, and 30.4 ng/mL at T12 (P<0.01)
- Ghrelin—56.4 pg/mL at baseline, 37.4 pg/mL at T3 (P<0.01), and 45.7 pg/mL at T12 (P<0.05)
Gene Expression Profiles
To better understand how LSG improved immune and metabolic profiles, the researchers performed RNA sequencing on blood samples from the first six participants. They looked for genes whose transcript counts were altered between baseline and three months after LSG.
The results revealed robust changes in gene expression in nearly all participants that influenced both immune function and immune metabolism. Gene expression patterns were quite similar between participants at baseline, with the exception of one subject. Intriguingly, that outlier patient responded poorly to LSG.
In the full cohort, the team evaluated the expression of a small set of genes of interest across all timepoints. At T3 and T6 they found a significant reduction of IGF2, part of a family of insulin-like growth factors involved in regulating insulin signaling and adiposity.
Laying the Groundwork
This study pinpointed alterations in several genes and gene pathways that merit further investigation in patients undergoing bariatric surgery:
- Downregulation of several cytokine pathways
- Downregulation of transforming growth factor-beta signaling
- Upregulation of several immunoglobulins
- Upregulation of oxidative phosphorylation, fatty acid oxidation and Myc signaling
- Downregulation of pathways related to estrogen response and heme metabolism, essential biological processes involved in signal transduction and immune cell survival
A better understanding of how bariatric surgery affects immunometabolism should lead to novel therapeutic strategies for treating obesity and related metabolic diseases.